Prostate cancer is the second leading cause of cancer death in American males. Although androgen therapy can temporarily control metastatic disease, most tumors become hormone refractory and then rapidly progress since there is no other effective therapy. Thus, there is an urgent need for new therapies. Prostate-specific membrane antigen (PSMA) is a well-characterized glycoprotein whose expression is largely restricted to epithelial cells. In normal tissues, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. But on tumor cells, PSMA contains a single transmembrane domain and a large extracellular domain. This cell-type specificity makes the large extracellular domain of PSMA an ideal candidate for immunotherapy. We propose development of anti-PSMA monoclonal antibodies for the treatment of prostate cancer. We have generated a panel of antibodies that recognize native, cell-surface PSMA. Antibodies will be purified and subsequently evaluated for specificity and antitumor properties in "naked" form and when conjugated to novel alpha- and beta-emitting therapeutic radionuclides. The lead candidate(s) identified in this proposal will be examined for efficacy in the best available models of human prostate cancer in Phase II in order to identify a lead candidate to advance into human clinical trials.